Interrogating the proteome of human tissue derived organoid culture to define mechanisms of gastrointestinal epithelial barrier injury in inflammatory bowel disease

Inflammatory bowel disease (IBD) including Crohn’s disease and ulcerative colitis affects over half a million people in the UK. It is caused by chronic inflammation in the gut, there is no cure and medications are not effective for all. There is a clinical need to understand why individuals develop this condition to help identify new treatment targets.

The gut is lined by a single layer of specialised cells (collectively called the gastrointestinal epithelial barrier) that separates the underlying tissues from the bowel contents. Injury and leakiness of this epithelial barrier is found in IBD. Altered function of the barrier can predict risk of IBD relapse, demonstrating a key role in disease development, and alterations in epithelial genes are associated with IBD risk. This exciting translational science PhD project in IBD will characterise epithelial barrier structure and function in IBD. The student will use human tissue-derived advanced cell culture models of the epithelial barrier called organoids to uncover how these cells react to toxic signals, and how these cells repair. A new IBD treatment target to facilitate repair and restore structure and function of the epithelial barrier would be a new and exciting development for the treatment of IBD. Before this can be developed, we first need to better understand epithelial cell mechanisms of injury in the human epithelial barrier in the context of IBD. Traditionally, human gut epithelial cells were difficult to study. This has been revolutionised with the advanced technique of organoid culture. This offers a near-physiological human tissue experimental model by creating 3D and 2D monolayer crypt-forming epithelial structures in a protein matrix. Organoids, using protocols already established in the McLean lab, will be created from human gut tissue from people with and without IBD, and from inflamed and non-inflamed tissues. The student will assess cell responses to injury by looking at changes in the structure and behaviour of these gut cells. We will do this by assessing genes, the amount and function of different proteins, the structure of the mucus, and by measuring the leakiness of the barrier. This project will provide experience and skills in a wide array of laboratory methods including cell culture, advanced organoid culture, molecular methods including RNA extraction and qPCR, microscopy, proteomic analysis by quantitative mass spectrometry and data analysis. The student will work closely with the Tayside Tissue Biorepository, be trained in working with human tissue, and work alongside collaborators based at the School of Life Sciences at the University of Dundee to acquire expertise in proteomics and data analysis (Prof Simon Arthur, Dr Andy Howden). Overall, we aim to identify new knowledge of why IBD develops and identify new ways of treating this condition. 

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